Among all newly discovered chemical
entities, about 40% are lipophilic and fail to reach the market due to their
poor water solubility.1 And the future pipeline is estimated to comprise
90% poorly soluble compounds, according to Bryan Wiesner, Director, External
Development and Outsourcing, AbbVie.

Solubility issues complicate drug
delivery, but there is an array of techniques available to enhance solubility and
improve the bioavailability of these drugs. This annual Drug Development
& Delivery report highlights many of those techniques, how to determine
the right technique for your compound, and how some pharmaceutical companies
are realizing faster time to market as a result.

Hot-melt extrusion (HME) is a proven, enabling
technology for enhancing the bioavailability and solubility of solid oral doses,
including potents. AbbVie was an early adopter of HME technology for
formulation development and dosage form for several reasons:

-As a solvent-free technology, it is
environmentally friendly;

-Once developed, it is an extremely robust
and reliable process;

-Continuous processing makes it a more
economical method of manufacturing;

-It is accepted by regulators
globally; and

-It has applications for abuse
deterrence and taste masking.

“HME, an amorphous dispersion
technology, uses pharmaceutical-grade polymers to formulate insoluble or poorly
soluble drug molecules,” says Mr. Wiesner. “This dissolves and distributes the
API through a specialized matrix, using heat and shear energy, to form a solid
solution of known potency and uniformity. This improves efficacy and drug delivery
efficiency. The extrudate can be subsequently formed into tablets, multilayer
tablets, and capsules, even with advanced profiles like dual API in a single
dose or API coatings on a core.”

HME has been used to improve drug performance
and patient compliance by reformulating drugs as controlled or modified release
to reduce daily dose requirements, or, for example, to avoid the need for
refrigeration or substantially reduce daily pill burden rates, says Mr.
Wiesner.

The challenges facing the successful formulation
of poorly soluble, lipophilic active pharmaceutical ingredients (APIs) can be
complex and multifactorial. Perhaps the most critical barriers to overcome in a
successful formulation are enhanced drug permeation and increased
bioavailability of the active. While there are approaches capable of improving
drug dissolution, there are relatively few that can improve drug permeability,
claims Dr. Donald Kelemen, Head of Corporate Business Development, ABITEC Corp.
Rarer still are excipients that improve dissolution and permeability, are part
of normal human physiology, and are capable of negating the food effect and
protecting the API from degradation in the GI tract. “Functional lipid
excipients can provide for all of these benefits,” says John K. Tillotson, RPh,
PhD, Pharmaceutical Technical Business Director, ABITEC Corp. “By dissolving
the API in a lipid-based preconcentrate, an oil-in-water emulsion can be
generated in the GI tract with the active ingredient molecularly dissolved or
dispersed in the lipid phase of a micellar system.” Depending upon composition,
these micelles can offer several functional advantages, including serving as a
protective environment for the API, instilling permeation enhancement for polar
actives through reversible tight junction modulation, and as a substrate for
mitigating the impact of Pglycoprotein efflux.

ABITEC develops lipid-based excipients
to enhance bioavailability of poorly water soluble and poorly permeable
molecules for the pharmaceutical industry. The excipients are manufactured in
accordance with strict cGMP and applicable IPEC (International Pharmaceutical
Excipient Council) guidelines in ISO-certified facilities. Recently, ABITEC has
expanded its manufacturing capabilities to provide greater flexibility to serve
our customers throughout development from preclinical to commercialization.

“ABITEC supports the needs of the formulators
by developing and providing applications research, investing in manufacturing agility,
and innovating to develop new product lines that meet the changing demands of
our customers,” says Dr. Tillotson. “Through research partnerships with major
universities, we develop new applications papers and guidance on solubility, phase
behavior, and permeability of functional lipid formulations that are available to
formulators and provide a starting point for formulation development.”

With the increasing number of new chemical
entities that may belong to BCS Class II and IV, a formulator rarely gets the opportunity
to develop a simple oral solution. The high number of poorly soluble compounds
in the industry is leading to the growing need for developing enabling technologies.
Understanding the chemical and preformulation property of the API is the first
step toward identifying a suitable enabling technique to enhance solubility or
bioavailability. Underlying variables and their relationship to product
performance and manufacturing needs are also important considerations. A
systematic approach for handling formulation issues is required.

A primary driving factor for
determining the best formulation approach is to assess the dose/solubility ratio,
explains Amol Matharu, PhD, Senior Director, Pharmaceutical Development, AMRI.
The maximum absorbable dose is directly related to the solubility, absorption
rate, GI volume, and GI transit time. Physiology of the GI tract also plays an important
role. For example, the pH change during GI transit can induce precipitation of
weakly basic compounds (pKa > 6) and increase solubility for acidic ones
(pKa < 5). An experienced and qualified lab should be used to design the
biorelevant tests, such as dissolution conditions, to better estimate in
vivo product performance.

Identifying the conditions limiting
oral absorption is critical to elaborate the mitigating strategies. For a
dissolution rate-limited system, where the compound is not fully dissolved in
the absorption window (dissolution time is greater than transit time), mitigation
strategies include salts, a polymorphic form, particle size reduction, surfactants,
polymers, amorphous API, and complexation. In a solubility-limited absorption, where
there is incomplete exposure of the drug (absorbed dose is less than total dose),
the problems can be mitigated using lipids, a prodrug, solid dispersion, and
solid state forms. Finally, for permeability-limited absorption, where there is
poor absorption, the main strategies involve using prodrugs or permeability
enhancers.

Based on needs and the API properties,
some of the enabling techniques utilized include lipid-based drug delivery
systems, solid dispersions, nanoparticles, long-acting injectables, and solid
oral controlled release formulations. Several examples from AMRI’s experience:
A poorly soluble API at preclinical development was formulated as an oral solution
in Capmul/Labrasol for a tox study and a PK study; and a micronized API in
capsule was developed for a Phase I clinical study. In another case, to improve
bioavailability of a poorly soluble drug, a high-energy solid was evaluated in
which API was dispersed in polymers through spray drying. As illustrated in
Table 1, dissolution of API was modified by modulating drug:polymer ratio. A
blend-in-capsule formulation was developed using the high-energy solid for a
Phase I clinical study. In the third case, when cosolvents, lipids, surfactants,
and complexation techniques alone failed to improve the solubility of an API, a
combination approach was used to improve the solubility 80,000 fold, giving an
oral solution drug product using a measured balance of various excipients serving
defined roles — for example, a mix of dimethylacetamide, Labrasol, and Tween 20
or Tween 80. The formulation was physically and chemically stable and ready for
dosing in the preclinical study. In another project, suitable drug exposure was
maintained by formulating a long-acting injectable suspension. Careful modulation
of the zeta potential and mixing parameters yielded an elegant flocculated drug
product utilizing a rugged, reproducible, and scaleable manufacturing process.

Not all solubility problems
necessarily involve BCS class II and IV compounds. For instance, one project
involved developing a controlled-release tablet for an API that is highly
unstable and water soluble. While various matrix-forming agents were evaluated,
none were effective to achieve a target release period of 24 hours. “Exploiting
the chemical properties of the API, acid-derivatized complexing agents were
utilized to slow the release and achieve a stable product with a desirable
dissolution profile,” says Dr. Matharu.

As a specialty CDMO, Ascendia focuses on
creating formulation solutions for poorly water-soluble molecules. Some of the
newer approaches the company offers include nanoemulsions and solid-lipid nanoparticles.
“The goal with nanoemulsions is to dissolve and stabilize the drug in a suitable
oil vehicle, and then produce oil-in-water nanoemulsions using either a high-shear
homogenization or a micro-fluidization process,” explains Jingjun “Jim” Huang,
CEO of Ascendia.

Minimizing the amount of
co-surfactants and co-solvents required for long-term physical stability is a
key strategy. With solid-lipid nanoparticles, the surface area advantage of
nanoparticles is extended by having the drug homogeneously dispersed in a lipid
carrier before nanonization. An alternative is to coat a drug nanocrystal with
a lipidic material prior to final dosage form preparation. Both nanoemulsions
and nanoparticles can be administered orally or via injection. Solid lipid nanoparticles
are especially useful for long-acting injectable formulations of poorly soluble
drugs, he says.

“Many emerging pharmaceutical
companies have promising compounds that require novel delivery science to
achieve their bioavailability targets,” says Dr. Huang. “Ascendia helps clients
determine the best formulation approach by investigating multiple options.
While we have capabilities in spray-drying, hot-melt extrusion, ball-milling,
micro-fluidics, and homogenization, it is not always obvious which technical
approach will optimize a drug’s performance. Ascendia accelerates development
time by conducting formulation comparisons and selection in parallel.”

Combinations of excipients and
approaches can lead to new intellectual property for a drug’s formulation. For
example, for one client, Ascendia developed a nanoemulsion formulation of a
drug that has only 3ng/ml water solubility. This drug exhibited significant
dose proportionality and food-effect issues. Ascendia experimented with a
matrix of oils and surfactants to develop several prototype formulations. In
the oil phase of the nanoemulsion, drug solubility was achieved in the
30-100mg/ml range—a 1 million-fold improvement. Multiple formulations achieved
good chemical stability, physical stability, and water dispersibility. All of
the formulations produced nanoemulsions with droplets sizes less than 1μm, and
ranged from as small as 20nm to ~ 700nm. “This feasibility study yielded a
viable oral formulation for the client that is now being tested clinically to
determine the improvement in dosing kinetics and the elimination of the
food-effect,” Dr. Huang says.

BASF: Excipient/API
Combinations That Expedite Drug Development

Solubility of new chemical entities
has been a key issue in drug molecule development. As discovery of more
insoluble compounds continues, the industry is adopting more innovative
formulation technologies to overcome the solubility and bioavailability challenges
to make them commercially viable and FDA compliant. These new approaches are
opening doors to more than 80% of NCEs in the pipeline that would otherwise
have a modest chance of succeeding, says Shaukat Ali, PhD, Technical Support
Manager, BASF. These include solid and liquid dispersion technologies for the
development of tablets and soft gels, solvent-free temperature-controlled
hot-melt extrusion and shear stress-driven Kinetisol® solvent-based
spray drying and electro-spraying technologies. Lipid-based liquid dispersion
formulation technology, such as self-emulsifying and micro-emulsifying drug
delivery systems, is also employed for the more insoluble NCEs to speed up
development cycles.

BASF offers a range of excipients for developing
oral solid and liquid dosages. The basic screening of excipients is key to the
selection of the appropriate formulation technologies or platforms. BASF also
provides medium to high throughput API screening services for customers with a range
of excipient choices that provides them the flexibility to design the
appropriate solid or liquid formulation dosage.

“Excipients play an important role in formulation
and drug delivery, but their role is sometimes limited in certain dosage forms
because of regulatory restrictions,” says Dr. Ali. However, many excipients are
multifunctional and can give formulators options. For example, Kollidon®
VA64 is a film former–a dry binder–used in both direct compression and roller
compaction, and also acts as a solubilizer in the melt extrusion of poorly
soluble compounds. Kollicoat® IR, a graft copolymer of polyethylene glycol
and polyvinyl alcohol, is used as an instant-release coating polymer as well as
a wet binder.

“Excipients like Kollidon VA64 and Kollicoat
IR are available commercially and have been used in oral solid, liquid, and
topical formulations,” says Dr. Ali. “Novel excipients, such as Soluplus®,
address the specific requirements of APIs where standard excipients are not as
effective.”

He continues: “Our technical and
processing know-how and the understanding of excipient chemistries and
functionalities enable formulators to efficiently identify the optimal
API/excipient combination that expedites drug development,” says Dr. Ali. “For instance,
to identify the appropriate polymers or solubilizers for solid or liquid dispersions,
screening a broad range of excipients from our portfolio is important to select
the ideal candidates for an optimal formulation.”

Capsugel helps customers formulate and
advance challenging compounds in many ways. Its core approach to product development
accounts for three interconnected themes: Upfront rational formulation design
that is based on science, the needs of the molecule, and the needs of the
finished dosage form. “This approach translates to greater speed to clinic and
market, while our focus on rational design is well suited to meet the market’s
demand for more specialized products for specific patient population groups,”
says Hywel Williams, PhD, Principal Scientist, Research and Development, Capsugel.

Capsugel’s range of enabling
technology addresses slow dissolution rate and/or low solubility (often linked
to low oral bioavailability) or to modulate the pharmacokinetic profile of a
compound. “We have strategically invested to support client programs from early
development through clinical testing and into commercial manufacturing,” says
Dr. Williams. “Having a vertically integrated offering can also minimize
program complexity and risk by avoiding potentially problematic technology transfers
during scale-up.”

Ensuring that a client’s compound is sufficiently
bioavailable via the oral route has many dimensions--and is sometimes not
limited to addressing dissolution rate or low solubility--requiring that other
biopharmaceutical aspects be considered. For example, achieving high
bioavailability combined with low variability and minimal local toxicity may
require one or more of the following approaches:

-Transient increases in intestinal
permeability, e.g., for compounds that are large/ionizable/efflux transporter
substrates;

-Recruitment of the bile salt/phospholipid
conduit to boost absorption in the fasted-state to mitigate food-effects;

-Targeting of a specific gut segment
to exploit a compound absorption window;

-Bypass a specific gut segment to
minimize local irritation or compound degradation, or to maximize local
compound effects in lower GI segments; and/or

In addition to broadening its
understanding of formulation, biopharmaceutics, and processes, Capsugel is
investing to expand the formulation and processing space of its core
technologies to meet the wider requirements of customers. These include
lipophilic salts for increased dose loading using lipid-based formulation
approaches, and spray dried dispersion “Hot Process” technology for compounds
with low organic solvent solubility.

As the cost of drug development rises,
and as companies look to develop drugs for smaller populations, there is
pressure to do more with less, to make decisions with the minimum of data and
without delay, and to try to manage the inevitable risks. This often means
relying on well-known and predictable approaches. But drug companies look to
new technologies to provide patent protection, protect the value of their
investment in the long term, or to widen the net where standard technologies
have been tried and unsuccessful.

Catalent has assembled a range of enabling
technologies to support these developments. Platform screening protocols help
quickly and inexpensively collect data to determine which approaches are most suitable
and which molecules have inherent issues that need to be resolved. “To enhance collaborative
scientific development between Catalent, its customers, and partners, we have
created a new Science and Technology function to accelerate the development of
drug products through the use of advanced formulation and drug delivery
technologies,” explains Stephen Tindal, Director, Science and Technology at
Catalent.

To help companies at the early stage of
formulation development, a platform screening protocol called the OptiForm®
Solution Suite combines preliminary formulation development with a molecule
preformulation screen. This provides customers with a “toolkit” for improving
the bioavailability of poorly soluble drugs using a range of bioavailability-enhancing
technologies, including the OptiForm API salt form, particle engineering,
lipid-based formulations, and amorphous dispersion.

At the pre-formulation stage,
Catalent’s OptiForm API solid form optimization includes salt form screening to
optimize solubility and stability, as well as polymorph screening to optimize
the crystalline form. Originally developed by GlaxoSmithKline, Catalent has
refined OptiForm API screening to help more customers speed the development and
optimization of their drug molecules. It offers a high throughput platform for
salt, crystal-form, and co-crystal screening, and has been applied to more than
500 compounds, spanning from early-stage lead compounds through launched products.

“Our platform screening protocols use minimal
amounts of API, are completed quickly, thus saving money,” claims Mr. Tindal. Using
OptiForm Solution Suite, customers receive a summary of study results, recommendations,
and risk assessment for each dose form option to yield better bioavailability.
These include operational considerations, regulatory approval risks, and
patient specific considerations. A dedicated scientific advisor works with the customer
to review all the data and make recommendations for the customer’s team. At the
end, the customer receives materials for use in animal pharmacokinetic studies,
which can include lipid solutions and/or suspensions, milled solid dispersions,
and micronized/milled salt form.

As an example of how Catalent worked
with a client to improve bioavailability, consider the case of Trio Medicines Ltd.
The company was progressing a prodrug API with poor bioavailability through Phase
1. The formulation was sub-optimal. The molecule was classified as BCS Class II.
The challenges were limited molecule characterization, fast turnaround, and limited
budget. Trio was looking to increase the Area Under Curve (AUC) by three to five
times and improve the formulation’s robustness. Catalent data revealed that the
molecule should be classified as a Developability Classification System (DCS) IIa
(i.e. limited by rate of dissolution rather than absolute solubility) with some
stability issues (not uncommon for a prodrug). In this study, three of the four
candidate formulations showed improved AUC potential. Trio would like to
increase AUC further, and is considering its options before deciding on the
best formulation with which to proceed.

In order to improve the performance of
a poorly soluble API, it is imperative to formulate a dosage form in a way that
enables the API to readily enter solution and be absorbed by the body.
Excipients play vital roles in providing functionality to the final drug
product to achieve this goal. “For example, through stabilizing the compound in
a high energy state for an amorphous solid dispersion, imparting hydrophilicity
to the dosage form to promote dissolution, and maintaining dissolved drug in solution
to allow for absorption, the API performance can be enhanced,” says Elizabeth J.
Tocce, Associate Research Scientist, Dow.

Dow Food, Pharma and Medical has introduced
a line of excipients to enable formulations of poorly soluble drugs to meet their
end targets through not only final dosage form performance but also improved use
in manufacturing technologies. The AFFINISOL™ polymers are cellulosic
derivatives designed specifically for hot-melt extrusion and spray drying
applications. “The AFFINISOL portfolio includes a novel grade of hypromellose,
AFFINISOL HPMC HME, that has advantageous thermal properties for hot-melt extrusion
and improved solubility in organic solvents for spray drying applications,” explains
Kevin P. O’Donnell, Associate Research Scientist, Dow.

In addition to the novel hypromellose,
there is also AFFINISOL HPMCAS, which is offered in three standard
acetate/succinate substitution grades. “HPMCAS, with custom acetate and
succinate substitutions tailored to an API to ensure the optimal performance, is
supported through a scalable cGMP market development plant,” says William W.
Porter III, Associate Research Scientist, Dow.

Additionally, Dow Food, Pharma and Medical
has technology capabilities and expertise to further assist formulators in developing
a robust drug product. In-house high throughput screening techniques can enable
rapid identification of the ideal polymer(s) and drug loading to formulate a
stable solid dispersion with optimum performance. Once identified, a
formulation can be translated to the desired manufacturing technology. For
example, a formulation selected for hot-melt extrusion can be further developed
at the laboratory scale for process parameter selection, which is confirmed
through scale up when needed.

Evonik recently launched EUDRATEC®
PEP technology, a versatile formulation toolbox where challenging actives
(peptides, proteins, BCS II, III and IV compounds) and functional ingredients
are combined in a modular way to meet targeted therapeutic needs. Dr. Firouz
Asgarzadeh, Director of Technical Services, Formulation and Application
Services, Health Care, Evonik Corp., says that Evonik’s EUDRAGIT® polymers
have been used to facilitate the delivery of the active ingredients to a
predetermined area of the GI tract, as well as for all types of controlled drug
release profiles.

“Functional excipients like EUDRAGIT polymers
have revolutionized the concept of excipient use in the pharmaceutical
Industry. They allow for the successful development of products with improved
bioavailability, targeting, and/or patient compliance,” says Dr. Asgarzadeh.

Additionally, to support customers in minimizing
the number of screening experiments and in the selection of the appropriate combinations
of pharmaceutically approved polymers with actives to form solid dispersions,
Evonik has developed a sophisticated platform called MemFis® (Melt Extrusion
Modeling and Formulation Information System). “MemFis uses solubility parameter
calculations and hydrogen bond formation probabilities to screen approximately 30
different polymers in combination with the API to identify the best initial
approach for formulating a solid dispersion.”

When screening solid dispersion
formulations, MemFis allows the selection of the most effective formulations
with a minimal number of experiments (typically 3-5) instead of random mixing
and matching of hundreds of polymer-drug combinations in an empirical approach.

Evonik has also invested in hot-melt extrusion
and spray drying equipment in several of its technical centers to help clients
with feasibility studies and formulation development based on MemFis results. “The
objective is to offer clients a “first time right” approach to formulation
development, enabling shortened development times as compared to conventional
random screening methods with a myriad of trial experiments outside of the
appropriate design space. This systematic approach saves money and significantly
reduces time to market.”

Evonik has applied MemFis to numerous customer
projects. In one recent study, MemFis was used for a company developing a
generic version of an existing commercial HME drug product. “The results from
MemFis directed us to a polymer that was not utilized in the original brand
product formulation,” explains Dr. Asgarzadeh. “Both the initial in vitro dissolution
and stability studies exhibited better performance of the “super generic”
version relative to the branded product. The client is continuing further clinical
studies with Evonik’s new formulation proposal.”

Under a recently formed collaboration with
Medimetrics, Evonik offers a combination of controlled delivery options, invivo delivery measurements via wireless communications, and data
interpretation with a single-use capsule that is swallowed, called Intellicap®.
This service conducts site absorption studies to precisely identify where the
drug is best absorbed along the GI tract. Based on the results from these studies,
the targeted development of oral controlled release formulations with increased
bioavailability can proceed more rapidly, says Dr. Asgarzadeh.

The indisputable fact before the
pharmaceutical industry is that a majority of emerging APIs suffer from
bioavailability issues attributed to poor solubility, dissolution rate, intestinal
permeability, and food effect. A growing number of these compounds are peptides
and macromolecules with upward inclination for molecular size, LogP value, and
sensitivity to pH and ionization, which may also become substrates for
intestinal transporters and enzymatic degradation in the GI tract, explains
Jasmine Musakhanian, Scientific & Marketing Director, Gattefossé.

“Hydroalcoholic solvents may improve the
drug solubility in the dose but are likely to fail in maintaining the drug in a
solubilized state in vivo,” she says. “Traditional approaches like drug
micronization or salt formation may offer tangible but limited value for a
small number of drugs. As each API presents its own unique set of challenges,
early consideration to the science, timing, and choice of technology becomes
critical.”

Among the fully developed and in-
creasingly popular approaches to bioavailability enhancement is the lipid
formulation approach, which is seconded by polymer-based solid dispersion
technologies. “Lipid-based formulations are leading the way for bioavailability
enhancement because of their unique ability to simultaneously improve intrinsic
solubility, enhance solubilization and supersaturation of API invivo,
and to protect the API against precipitation or binding to enzymes in the GI
tract,” says Ms. Musakhanian. “Unlike solid dispersion approaches that require
extensive kinetic stability studies, lipid formulations are much easier to
develop in soft or hard gelatin capsules. Easy to manufacture and readily
scalable, they offer significant savings in development time.”

An important and often overlooked benefit
of lipid formulations is mitigation of the food effects associated with more than
80% of poorly soluble drugs. Food effect can lead to significant issues during clinical
development and post market safety and patient compliance, requiring drug label
warnings of intake with meals or on an empty stomach. Gattefossé specializes in
lipid excipients and formulations for addressing drug solubility and bioavailability
in oral, topical, and other routes of administration.

Gattefossé offers Preclinical
Guidelines for early drug development stages, detailing the appropriate
excipient dose per animal model. “Our customers can also tap into our Oral Bioavailability
Guidelines where we provide step-by-step approaches to identifying and
selecting the most promising combination of drug with excipient(s), how to
determine stability and miscibility of excipient mixtures, their particle size
dispersion, and in vitro lipolysis assays to help predict the in vivo
performance of prototype formulations,” says Ms. Musakhanian.

Gattefossé has worked with global organizations
toward the development of predictive tools such as lipolysis (lipid digestion) testing
that can help predict the potential in vivo behavior of the lipid
formulation in humans. “This in vitro test brings to the fore
significant time and cost savings associated with animal testing, which
incidentally is not always predictive of bioavailability in humans,” she says.

iCeutica: Accelerate
Development of New Chemical Entities

Mechanical particle size reduction of the
drug substance is a well-known method of increasing the surface area, thereby
increasing the dissolution rate of a poorly soluble compound. Jet milling is
the most common and widely available method of particle size reduction, but it
is limited to reducing average particle size to 3-10 micron, and the powder is
typically difficult to work with due to high static and low bulk density. Wet
media milling can yield submicron drug particles, which are stabilized with
excipients in an aqueous suspension. The drawback to this technique, says Dr.
Maura Murphy, Senior Director of Pharmaeutical R&D, iCeutica, is that the
water must be removed by a lengthy granulation process. There are some marketed
compounds utilizing this technique, including sirolimus (Rapamune®)
and aprepitant (Emend®).

It is also possible to produce
submicron drug particles utilizing a dry media milling process, which removes
the difficulties of the wet media milling process while achieving similar benefits.
iCeutica’s SoluMatrix Fine Particle Technology™ is an attritor milling process
utilizing ball media and inert GRAS excipients to grind the active to a
submicron particle size. Through this low-energy milling process, the
excipients that help grind the drug substance remain at 2-10 micron, while the
active is reduced to an average of 200-800nm. The excipients also serve to
stabilize the drug substance particle size. “In contrast to high energy milling
processes such as jet milling, the attritor milled powder has much less static
and has moderate bulk density, allowing for much easier handling,” she says.
The attritor milling process does not typically alter the drug substance
crystal structure, ensuring the product remains thermodynamically stable. This
technology has been utilized to optimize absorption in marketed compounds such
as diclofenac (Zorvolex®) and meloxicam (Vivlodex®). iCeutica
offers development services utilizing the SoluMatrix technology to improve the
dissolution rate of compounds for partner companies. iCeutica can conduct rapid
feasibility studies, as well as complete dosage form development, clinical
study management, and GMP manufacturing up to 150kg scale.

“Improvement of the dissolution rate can
enhance drug performance of poorly soluble compounds by improving oral bioavailability,
reducing the pharmacokinetic variability, and reducing or removing food effects,”
says Dr. Murphy. “A faster dissolution rate can also reduce the time to reach
pharmacodynamics effects for compounds with extended Tmax.”

Metrics Contract Services offers the ability
to manufacture spray-dried material or to micronize the API through jet
milling, both of which improving solubility and bioavailability and augment
Metrics scientists’ knowledge of formulating amorphous materials and nanoparticles.
The resulting material will be formulated as a capsule or a tablet.

When it comes to developing
challenging compounds, it helps if the scientists know whether the client has
performed preliminary solubility studies, any kind of simple animal PK studies,
or even what the critical quality attributes are, such as modified release or
the need to deliver the drug in the small intestine, explains Michael DeHart, PhD,
Developmental Scientist II, Metrics Contract Services. “Such information allows
us to move projects forward expeditiously without duplicating efforts.”

Also challenging is the sheer number of
excipients on the market, as well as the different grades available.
“Scientists at Metrics Contract Services work closely with our vendors’ sales
teams and technical support personnel to ensure that we are choosing the
optimal excipients from the beginning in order to expedite development,” says
Dr. DeHart.

One client brought Metrics a prodrug known
to be susceptible to acid degradation and general hydrolysis, which meant it had
to be protected from stomach acid. In addition, exposure time to fluid in the
small intestine needed to be minimal. “We took a two-pronged approach to
resolving these issues,” explains Dr. DeHart. “First, we knew an enteric coat
was essential to provide acid protection. Second, we incorporated muco-adhesive
polymers into the core tablet, which helped it adhere to the walls of the small
intestine. This allowed the prodrug to permeate across the small intestine,
where it then was hydrolyzed to the API. Despite the daunting challenge of
preventing hydrolysis throughout transit in the stomach and small intestine,
animal studies confirmed that we were able to provide bioavailability of the
molecule of interest.”

Two major factors in determining the success
of a drug are the delivery form and bioavailability. Both of these topics are
addressed by MilliporeSigma’s Actives and Formulation R&D activities.

“The interaction of new technologies and
excipients, as well as new formulation approaches, create an increasingly
complex scenario,” says Andrew Bulpin, Head of Process Solutions Strategic
Marketing & Innovation at MilliporeSigma. “A gap in support exists when
working with customers to establish formulation techniques and excipients within
their R&D platforms using their model APIs. Thus, MilliporeSigma offers pharmaceutical
developers support through counseling, hands-on training, and formulation development
at our “Formulation Center” at the Darmstadt site, and within our global service
network and collaboration centers (M Lab™ Collaboration Centers).”

As a manufacturer of excipients,
MilliporeSigma finds the right excipients to boost solubility of APIs, Mr.
Bulpin explains. “Poor solubility of small molecules as well as biomolecules is
multi-factorial and a one-size-fits-all approach is not applicable. Thus, providing
a comprehensive toolbox of products and addressing different solubility technologies
and solutions is a must.”

However, many of MilliporeSigma’s customers
are reluctant to use novel excipients, given the regulatory implications. To
this end, the company formulates these compounds with proven technologies and
excipients, ensuring a smooth path through the registration and approval
process, he says. “Our offering of more than 400 Emprove® excipients
is focused on exactly that.”

Excipients’ impact on API
bioavailability requires that scientists determine if the API can be formulated
with standard formulation technologies or if nonconventional formulation
approaches need to be employed. “MilliporeSigma is working with advanced
excipients (Parteck® product portfolio) and formulations that
support oral or alternative administration routes that meet the innovator’s
desire and increase the patient’s comfort,” says Mr. Bulpin. “We do this by
considering modified release approaches and the use of tablets, capsules, or
patches instead.”

Particle Sciences: A Range
of Solubilization Approaches Ensures a Right Fit

As formulation scientists know,
solubility is one of the key physicochemical parameters a formulator needs to
understand and manipulate in order to develop viable formulations. Particle
Sciences (PSI) has a number of solubilization approaches ranging from in
silico design, to nanoparticulate suspensions, to solid solutions, to lipid-based
systems such as LyoCells® (PSI proprietary reverse cubic and
hexagonal phase nanoparticulate delivery system). API characteristics will
determine which technology is best to use. For instance, a heat stable highly
potent compound with a positive logP naturally drives towards hot-melt
extrusion. “A relatively labile molecule with good lipid solubility may be a good
candidate for LyoCells, and a classic BCS II molecule should always be
evaluated for its amenability to be formulated as nanoparticulate suspensions,”
says Robert W. Lee, PhD, Vice President of Pharmaceutical Development Services,
PSI.

Recently, one of PSI’s clients had a need
to deliver a BCS II API across the blood brain barrier (BBB). “The API was crystalline
so we nanomilled it in order to increase its rate of dissolution,” explains Mark
Mitchnick, MD, CEO, Particle Sciences/CMO-Lubrizol LifeSciences. “We then developed
a nasal dry powder dosage form to facilitate delivery across the BBB. To
minimize potential delivery into the lungs, we spray dried the nanoparticulate
suspension in the presence of a larger, inert carrier to produce a mean
particle size on the order of 20m and also eliminated fine particles. This
approach worked very well and provided the highest in vivo API
concentrations into the brain in a primate study.”

In all of these methods, the
excipients play a key role. To increase the range of materials at its disposal,
PSI maintains strategic relationships with a variety of excipient suppliers,
such as with PLGA for use in polymeric nano- and micro-particulate formulations.
As part of Lubrizol Life-Sciences, PSI has access to a variety of polymers that
play a key role in the solubility of APIs such as thermoplastic polyurethane-based
technologies. “These relationships help speed our development whether the polymer
is used or not,” says Dr. Lee. “Sometimes even knowing what raw material won’t
work in a particular application helps to point us in the right direction more
quickly.”

And with the backing of its parent company,
Lubrizol, a Berkshire Hathaway Company, PSI is proceeding into commercial manufacturing
by breaking ground on modular commercial clean room space. “The versatile
design of our facility is conducive for the manufacturing of low-volume, high-value
complex products, such as nanoemulsions, polymeric nanoparticles, solid lipid
nanoparticles, and PLGA micro and nanoparticles,” says Ms. Glassco. The
facility will be commercial-ready in the third quarter of 2017 and the first
product will follow shortly.

Increasing solubility is only one part
of improving bioavailability of drugs. In order to increase flux of the drug
through a biological membrane, the permeability of the API through the membrane
has to be taken into account. Creating amorphous solid dispersions that
increase kinetic solubility of low-soluble compounds without decreasing their
effective permeability is one way to achieve higher bioavailability.

Pion Inc. provides a comprehensive suite
of physicochemical characterization services that help formulation scientists
develop the most-effective formulation in terms of its ability to get absorbed
through oral or other routes of administration. These include: ionization
constants (pKa) measurements, lipophilicity (logD/logP), solubility and permeability
in buffers and biorelevant media, in situ dissolution of
pre-formulations in buffers and biorelevant media, and flux measurements. Additionally,
Pion Inc. provides instruments and services that help pharmaceutical companies
answer key questions about the absorption potential of their drugs from the
early stages of formulation until the final stages of drug product development.

Excipients, formulations, and drug
delivery platforms are often intended to modify the rate and extent of
absorption with the goal of improving bioavailability. Understanding the effect
of excipients and formulations on physicochemical properties of API is critical
for developing a successful drug product.

In one example, a client provided five
different formulations in an attempt to select the most promising one for
further development, explains Konstantin Tsinman, Chief Scientific Officer,
Pion Inc. “Two formulations showed similar improvements in solubility and
dissolution while only one of these two demonstrated superior flux. It was
later confirmed by the client that the formulation selected based on flux
measurements performed the best in dogs.”

Quotient Clinical: Rapid
Formulation Development Optimizes Solubility

While industry has done a tremendous job
of developing excipients, formulations, and drug delivery techniques to improve
solubility, the question remains: Which is right for my program?

“There are many reasons as to why a
particular technology might be selected, including molecule properties and
therapeutic indication, but eventually a prototype formulation must be
developed and tested in some way,” says John McDermott, Executive Director,
Drug Product Optimization, Quotient Clinical. “Initially, laboratory analysis
and preclinical studies are used, but these methods are notoriously poor at
predicting drug behavior in humans. Often, performance remains sub-optimal when
the formulation is dosed to human subjects, and the development program is
further disrupted while additional cycles of formulation development and
clinical evaluation are performed.”

Mr. McDermott says that Quotient Clinical
has developed an innovative approach to identify and overcome these challenges,
which enables formulations to be designed, manufactured, and clinically evaluated
rapidly within a single organization. “Drug product can be manufactured within
7 days of dosing, removing stability package generation from the critical path
to obtain clinical data on product performance,” he says. Integrated GMP manufacturing
with clinical testing allows clinical data from one study period to be used in
order to select the product to be manufactured for evaluation in the next period.
This rapid formulation development and clinical testing (RapidFACT®)
approach permits biotech and pharma to select and optimize solubility enhancing
formulation technology such as spray dried dispersions, lipidic, and
nano-crystalline systems in human subjects, quickly, he says.

In one example, a client completed a Phase
1 clinical trial using an oral suspension of a spray-dried dispersion, but transition
to a solid oral dosage form was needed for further development. “In this case,
the sponsor had observed a lack of correlation between the in vitro and
preclinical models, so drug product selection was impossible without supporting
clinical data,” explains Mr. McDermott. “A Rapid-FACT program was designed to
develop a range of tablet prototypes based around the core spray dried
dispersion. Performance was compared in a rapid and flexible manner in human subjects.

This RapidFACT program evaluated a
range of solid oral dose options in the absence of a predictive in vitro or
preclinical model, and identified a suitable product for further clinical
development in less than 8 months. Mr. McDermott adds: “RapidFACT therefore
delivered significant time savings, with a total of 10 formulations evaluated
on the basis of human PK data in a clinical phase lasting less than 10 weeks.”